INTERVIEW WITH DR. ROBERT LIVINGSTON

DR. LOVE: Every San Antonio meeting seems to have at least one clinical trial report that not only directly impacts clinical decision-making but also causes researchers to rethink their strategies and in many cases to incorporate advances into the design of new clinical trials. One of the most discussed presentations at the 2000 San Antonio meeting was given by Dr Joyce O'Shaunessay, who reported on a response rate and survival advantage of the combination of capecitabine and docetaxel compared to docetaxel alone in metastatic disease. O'Shaunessay reviewed these inntriguing results on our Breast Cancer Update program last year. Many of the researchers interviewed for this series since then have commented not only on the implications of these data to treatment of women with metastatic disease but also on how these perhaps surprising results of capecitabine and docetaxel will effect the design of new adjuvant and neoadjuvant trials. There were a number of follow-up posters and presentations at this year's San Antonio meeting on the capecitabine-docetaxel study, and I met with Dr Robert Livingston to review the background and design of an intriguing new adjuvant Intergroup study that includes the capecitabine-docetaxel combination.

DR. ROBERT LIVINGSTON: The study is a trial that will be a Phase III randomized study in the adjuvant setting for patients with hormone receptor-negative, node-positive disease, and hormone receptor-negative, node-negative disease if the primary tumor has certain high-risk characteristics. It is a study that is built on the results of two pilot studies. Actually, one pilot study and one Phase III study in advanced disease. It will go forward as an Intergroup trial in the United States in the near future.

DR. LOVE: That'll be under which group, primarily?

DR. LIVINGSTON: The Southwest Oncology Group will be the lead group, because we have proposed it, and that's the group that I belong to. But all of the other major cooperative groups will participate: Cancer and Leukemia Group B, Eastern Cooperative Oncology Group and the North Central Cancer Treatment Group.
The PI for this study is going to be Dr. Tom Budd at the Cleveland Clinic.

DR. LOVE: What's your involvement with the study?

DR. LIVINGSTON: My involvement with the study is that my institution performed the pilot study that serves as the platform for the first question to be asked. After discussion with my colleagues and the other cooperative groups, I agreed with them that it was important to ask the second question based on the previous randomized trial.

DR. LOVE: Can you talk about the design of this new study and the background that led up to it?

DR. LIVINGSTON: The design is going to be a comparison of two different ways of giving AC, Adriamycin and cyclophosphamide, followed by a comparison of Taxotere alone to the combination of Taxotere and Xeloda. The initial randomization is based on observations from our group in Seattle that so-called continuous chemotherapy may be more effective than standard intermittent chemotherapy.

Basically what we've done is give Adriamycin on a weekly basis for a period of 20 weeks to a total dose of 480 milligrams per square meter. That was combined with cyclophosphamide given at 60 milligrams per square meter per day by mouth. In order to assure adequate dose intensity, the patients received GCSF, five micrograms per kilogram/per day for six days out of seven throughout the course of treatment. The growth factor was, in fact, given concurrent with the cyclophosphamide chemotherapy.

Our follow-up on this study has been presented and has now been submitted as a manuscript. Basically, we have a median follow-up in excess of five years, 64 months. We treated 53 patients with node-positive breast cancer and this was a trial aimed at patients with poor-risk disease, which was defined as having negative estrogen-progesterone receptor, HER2/neu over-expression, or having four or more positive lymph nodes. In that trial, with five years plus of median follow-up, 85 percent of the patients remain free of any evident recurrence.
The 95 percent confidence limits on that are from 75 to 95 percent. If you look at the expected result for standard AC given at 60 milligrams per square meter of adriamycin, and 600 milligrams per square meter of cyclophosphamide given every three weeks as it is done in the community and by the NSABP, the NSABP studies indicate an expected five-year disease-free survival of between 60 and 65 percent.

DR. LOVE: This is with comparable risk factors?

DR. LIVINGSTON: Well, we have analyzed the risk factors for our group. One has to bear in mind, first, that it's not a randomized trial and, second, that our numbers are small. But, with those caveats, the proportion of patients with one to three positive nodes, the proportion with four to nine positive nodes, and the proportion with 10 or more positive nodes is actually a little bit higher for the higher node groups in our study. In other words, there are more patients proportionately with four to nine positive nodes. The proportion with one to three and the proportion with 10 or more is identical. We looked at the proportion with estrogen receptor-positive disease, an obvious favorable prognostic factor. It was identical in our experience versus the NSABP; in other words, about two-thirds of the patients were estrogen receptor-positive.

DR. LOVE: And these women got tamoxifen, I'm assuming?

DR. LIVINGSTON: Those patients went on to receive tamoxifen. But no other chemotherapy was administered to these patients. What I've compared in terms of discussing the NSABP data is their studies, B-22 and B-25, in which no additional chemotherapy was given after Adriamycin and cyclophosphamide. The proportion of patients with HER2/neu overexpression in our study is 43 percent. The NSABP data do not provide that information, but I know that our study was intentionally enriched for patients who had overexpression of HER2/neu. Given the expected proportion of HER2/neu positive patients, I would guess that theirs is probably about half that.

DR. LOVE: What's the dose of Adriamycin?

DR. LIVINGSTON: The dose of Adriamycin was actually - the pilot study we did came in two pieces. The first piece, we did in the first two years, and the second piece, we did in the next two and a half years. The first piece, we actually give 5FU as part of the treatment program. So, they received 5FU on a weekly basis, Adriamycin on a weekly basis, and they received daily oral cyclophosphamide.

In that phase, the Adriamycin was given at 20 milligrams per square meter per week to a total dose of 480 milligrams per square meter. So, the total duration of treatment was 24 weeks. 5FU was given at 300 milligrams per square meter per week, and the Cytoxan, as I mentioned, at 60 milligrams per square meter per day.

That program was feasible, but it was associated with a high incidence of moderate hand-foot syndrome. Grade 2 hand-foot syndrome occurred in 55 percent of the patients. And we felt that that was due to an interaction between 5FU and weekly Adriamycin, both of which can produce hand-foot syndrome.

What we decided to do was to drop the 5FU and attempt to escalate the Adriamycin dose. And so the second phase of the study - the first phase involved 30 patients, the second phase involved 23 - we deleted the 5FU and patients received Adriamycin at 24 milligrams per square meter per week for a total of 20 weeks. So, the total dose of adriamycin is the same, 480 milligrams per square meter, but it was a little longer period to deliver that total dose when we gave it with the three-drug combination. Cyclophosphamide was the same. GCSF was the same in both of the regimens.

DR. LOVE: I heard the term metronomic chemotherapy.

DR. LIVINGSTON: Yeah.

DR. LOVE: Is that what this is?

DR. LIVINGSTON: Well, this may be metronomic chemotherapy. I would be not telling you the truth if I told you that we had designed it as metronomic chemotherapy, because these studies obviously began several years ago. At that time, I did not know what the term metronomic chemotherapy meant. But if one means by metronomic chemotherapy that there is more or less continuous exposure of tumor cells and/or endothelial proliferative cells to potentially effective cytotoxic concentrations, the answer is yes, because the beta half life of adriamycin is a matter of days. And through that whole beta half-life, one achieves potentially therapeutic concentrations. The half-life of cyclophosphamide is about 12 hours. By giving daily cyclophosphamide, one obviously achieves a more or less continuous blood level of the active metabolites of that drug. So, yes, I think that, although it was not constructed to be metronomic chemotherapy, in fact, the regimen is metronomic.

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